For Fulvestrant, Higher Dose Is Better

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Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Increasing the dose of fulvestrant from 250 to 500 mg improved the median overall survival in women with locally advanced or metastatic estrogen receptor-positive breast cancer without increasing toxicity.

SAN ANTONIO -- Women with recurrent or metastatic hormone-sensitive breast cancer lived longer when they received a higher dose of the endocrine therapy fulvestrant, according to data reported here.

Median overall survival improved by more than 4 months among women treated with a 500-mg dose of fulvestrant instead of the usual 250-mg dose. The difference represented almost a 20% reduction in the mortality hazard.

The higher dose did not significantly increase the risk of serious adverse events, Italian oncologist Angelo Di Leo, MD, said during a press conference at the San Antonio Breast Cancer Symposium.

"These results are consistent with the previously reported progression-free survival and overall survival data," said Di Leo, of the Hospital of Prato. "The safety results do not support any clinically relevant difference between fulvestrant 250 and 500 mg, and they are consistent with the previously reported safety profile of fulvestrant 500 mg.

"Based on the results of the present trial, whenever fulvestrant is considered for the treatment of menopausal patients with estrogen receptor-positive advanced breast cancer, the recommended dose is 500 mg."

The findings came from a follow-up analysis of the CONFIRM (Comparison of Faslodex in Recurrent or Metastatic Breast Cancer) trial. Three years ago, Di Leo and colleagues reported that the higher dose of fulvestrant was associated with significantly better progression-free survival (PFS), which was the trial's primary endpoint. At that time, the data showed a trend toward improved overall survival.

The earlier analysis occurred after half the patients had died. In an effort to confirm a potential survival benefit, the investigators decided to continue follow-up and re-analyze overall survival after 75% of the patients had died.

The impetus for CONFIRM came in part from some breast cancer specialists' suspicion that fulvestrant's approved dose of 250 mg was inadequate.

The estrogen receptor antagonist has been available for more than a decade but has attracted less attention than other hormonal therapies developed at the same time and since. After the PFS data from CONFIRM were reported, some observers speculated that suboptimal use -- including dosing -- had figured into the drug's relatively modest following among cancer specialists.

A randomized, multicenter, phase III trial, CONFIRM involved 736 women with estrogen receptor-positive breast cancer that had progressed or recurred after treatment with an anti-estrogen or an aromatase inhibitor. The patients were randomized to one of the two doses of fulvestrant and followed until progression or death.

The primary analysis showed a 1-month improvement in median PFS in the group that received the higher dose of fulvestrant (6.5 versus 5.5 months, P=0.006). Analysis of overall survival, one of several secondary endpoints, showed a 3-month improvement with fulvestrant, but the difference did not achieve statistical significance (P=0.091).

With longer follow-up, the survival difference had increased to more than 4 months, representing a 19% reduction in the hazard ratio for the 500-mg versus 250-mg dose (P=0.016). Di Leo emphasized that the P value came from an unadjusted analysis and should not be considered a true representation of statistical significance.

However, he also pointed out that the updated survival analysis is consistent with the earlier results showing a trend toward improved survival with the 500-mg dose of fulvestrant. Di Leo also stood by his assertion made 3 years ago that the 500-mg dose should be considered the standard dose.

The safety analysis showed that serious adverse events occurred in 9.7% of the 500-mg group and 7.2% of the 250-mg group. Rates of drug-related serious adverse events were 2.2% and 1.1%, respectively. Adverse events proved fatal in five patients treated with the 500-mg dose of fulvestrant versus seven in the 250-mg group.

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